Exposure to early abuse is a major risk factor for the development of depression. Over the last several years we, and others, have shown that childhood abuse is associated with alterations in brain structure. Recently, we hypothesized that different brain regions have their own individual neurodevelopmental sensitive periods when they are maximally susceptible to the effects of early stress, and have published the first preliminary findings that support these hypotheses. In particular, we found that the hippocampus, corpus callosum and frontal cortex were maximally vulnerable at 3-5, 9=10 and 14-16 years of age, respectively. In addition we hypothesized that the psychiatric sequela of abuse would depend, at least in part, on the timing of the stressor in relation to regional sensitive periods. The aims of this program of research is to ascertain if these preliminary findings of regional neurodevelopmental sensitive periods can be replicated, extended to males and to other forms of adversity besides childhood sexual abuse. Second, we will test our hypothesis that there are discrete sensitive periods when exposure to abuse or loss is maximally associated with risk for developing depression. Further, we will test the hypothesis that sensitive periods for the development of depression overlap with windows of vulnerability for left hippocampus and portions of prefrontal cortex, and will also ascertain if other brain regions have windows of vulnerability that overlap with the sensitive period for depression. Next we will test the hypothesis that hereditary factors increase risk for depression, in part, by amplifying and extending the sensitive period for depression. Finally, we will test the hypotheses that early exposure to tolerable stressors will help to inoculate unexposed child hosts from developing depression if they are subsequently exposed during the sensitive period. Further, experiences that foster neurogenesis, facilitate strong feelings of self-esteem or provide a supportive social network will help to preempt the emergence of depression in exposed hosts. These hypotheses will be tested in a sample of 600 individuals (20-25 years of age, ~50% male) recruited from the community. Degree and timing of developmental exposure to abuse and loss across each childhood stage will be quantified retrospectively using a modified Adverse Childhood Experience score. Neurodevelopmental sensitive periods will be evaluated in 200 of these subjects from volumetric T1 and T2 scans and diffusion tensor images. This information will greatly enhance our understanding of the genesis and etiology of major depression and may provide critical insights necessary to design programs to prevent or preempt the development of depressive disorders. PUBLIC HEALTH RELEVANCE: Exposure to early abuse alters trajectories of brain development and is a major risk factor for the development of depression. We will test the hypothesis that the psychiatric consequences of exposure to early abuse and loss depend on the timing of the stressor in relationship to neurodevelopmental sensitive periods, which are influenced in amplitude and timing by hereditary factors and modulated by protective factors.